The role of glutathione turnover in the apparent renal secretion of cystine.
Previous studies with cystinuric dogs and humans have demonstrated that the amount of cystine excreted in the urine is, in some cases, larger than the amount of cystine removed from the plasma by glomerular filtration. It was concluded that the kidney must secrete cystine into the renal tubule. The present studies indicate that renal glutathione turnover constitutes a mechanism of cystine secretion which may account for a large fraction of the cystine burden in the mouse renal tubule. Mice administered L-arginine or L-lysine, inhibitors of cystine transport, excrete large amounts of cystine in their urine (approximately 15 mumol of cystine/mg of creatine). If the mice are pretreated with buthionine sulfoximine, an inhibitor of glutathione biosynthesis, glutathione turnover is substantially decreased, and the arginine- or lysine-induced cystinuria is reduced by 43 to 55%. The plasma cystine concentration following arginine or lysine administration is reduced less than 15% by buthionine sulfoximine. These findings suggest the in vivo operation of a cycle in which glutathione, synthesized from cysteine intracellularly, is transported into the tubule and oxidized to glutathione disulfide. Subsequent breakdown of glutathione disulfide by gamma-glutamyl transpeptidase and dipeptidase releases cystine within the tubule. In the absence of cystine transport defects or inhibitors, cystine is reabsorbed and reduced intracellularly to cysteine.
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D019328:Buthionine Sulfoximine; D003553:Cystine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice
D000596:Amino Acids; D008717:Methionine Sulfoximine; D003553:Cystine; D019328:Buthionine Sulfoximine; D001120:Arginine; D005978:Glutathione; D008239:Lysine